CSAHi study: Detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes

Kitaguchi, Takashi; Moriyama, Yoichi; Taniguchi, Tomohiko; Maeda, Shinji; Ando, Hiroyuki; Uda, Takaaki; Otabe, Koji; Oguchi, Masao; Shimizu, Shigekazu; Saito, Hiroyuki; Toratani, Atsushi; Asayama, Mahoko; Yamamoto, Wataru; Matsumoto, Emi; Saji, Daisuke; Ohnaka, Hiroki; Miyamoto, Naokazu

doi:10.1016/j.vascn.2017.02.001

Cited by 38 publications

(25 citation statements)

References 39 publications

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“…As expected, an increase in the beat rate along with a decrease in beat period and FPDc was observed in both the 2D as well as the 3D cultures after ISO treatment. Our observations are consistent with previous studies, where a dose-dependent increase in contractility was observed in 2D cultured hiPSC-CMs following treatment with ISO (Mehta et al, 2011;Blazeski et al, 2012;Kitaguchi et al, 2017), as a result of β1 and β2 receptor stimulation. Additionally, although VER has been known to inhibit voltage-dependent calcium channels (Harris et al, 2013), an increase in contractility was observed in both 2D and 3D cultures.…”

Section: Discussionsupporting

confidence: 93%

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Kumar

Sridharan

Palaniappan

et al. 2020

Front. Bioeng. Biotechnol.

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Recent advances in cardiac tissue engineering have shown that human inducedpluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cultured in a threedimensional (3D) micro-environment exhibit superior physiological characteristics compared with their two-dimensional (2D) counterparts. These 3D cultured hiPSC-CMs have been used for drug testing as well as cardiac repair applications. However, the fabrication of a cardiac scaffold with optimal biomechanical properties and high biocompatibility remains a challenge. In our study, we fabricated an aligned polycaprolactone (PCL)-Gelatin coaxial nanofiber patch using electrospinning. The structural, chemical, and mechanical properties of the patch were assessed by scanning electron microscopy (SEM), immunocytochemistry (ICC), Fourier-transform infrared spectroscopy (FTIR)-spectroscopy, and tensile testing. hiPSC-CMs were cultured on the aligned coaxial patch for 2 weeks and their viability [lactate dehydrogenase (LDH assay)], morphology (SEM, ICC), and functionality [calcium cycling, multielectrode array (MEA)] were assessed. Furthermore, particle image velocimetry (PIV) and MEA were used to evaluate the cardiotoxicity and physiological functionality of the cells in response to cardiac drugs. Nanofibers patches were comprised of highly aligned core-shell fibers with an average diameter of 578 ± 184 nm. Acellular coaxial patches were significantly stiffer than gelatin alone with an ultimate tensile strength of 0.780 ± 0.098 MPa, but exhibited gelatin-like biocompatibility. Furthermore, hiPSC-CMs cultured on the surface of these aligned coaxial patches (3D cultures) were elongated and rod-shaped with well-organized sarcomeres, as observed by the expression of cardiac troponin-T and α-sarcomeric actinin. Additionally, hiPSC-CMs cultured on these coaxial patches formed a functional syncytium evidenced by the expression of connexin-43 (Cx-43) and

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Section: Discussionsupporting

confidence: 93%

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Kumar

Sridharan

Palaniappan

et al. 2020

Front. Bioeng. Biotechnol.

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“…hSC-CMs have been shown to display cellular electrophysiological properties that are often similar to human primary cardiomyocytes, including ionic currents, channel gating properties, ventricular-like action potentials, and expected sensitivity to multiple drugs (Bett, et al, 2013;Honda, Kiyokawa, Tabo, & Inoue, 2011;Ma, et al, 2011;Peng, Lacerda, Kirsch, Brown, & Bruening-Wright, 2010). A variety of approaches have been utilized in hSC-CM based assays, including patch clamp, microlectrode arrays, optical indicators of voltage, mechanical movement, cellular impedance, Ca 2+ transients and others (Ando, et al, 2017; A C C E P T E D M A N U S C R I P T -6 -Asakura, et al, 2015;Blinova, et al, 2017;Gossmann, et al, 2016;Guo, et al, 2011;Guo, et al, 2013;Kitaguchi, et al, 2017;Leyton-Mange, et al, 2014;Lu, et al, 2017;Lu, et al, 2015;Nunes, et al, 2013;Pfeiffer, et al, 2016;Pfeiffer, et al, 2017;Piccini, Rao, Seebohm, & Greber, 2015;Puppala, et al, 2013;Scott, et al, 2014;Sirenko, et al, 2013;Sun & Nunes, 2016;Zeng, Roman, Lis, Lagrutta, & Sannajust, 2016). These studies have provided promising evidence that hSC-CMs are a relevant cell model to study drug-induced cardiac abnormalities, including arrhythmia and QT prolongation, and display good in vitro concordance to clinical findings.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms

Pfeiffer-Kaushik

Smith

Cai

et al. 2019

Journal of Pharmacological and Toxicological Methods

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“…Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) have been applied to cardiac safety assessment in the non-clinical stages of drug development. Human iPS-CMs express fundamental cardiac ion channels and can generate action potential (Honda et al, 2011;Ma et al, 2011), which makes them a useful nonclinical tool for assessing the proarrhythmic potential of drugs (Ando et al, 2017;Kitaguchi et al, 2017;Takasuna et al, 2017;Nozaki et al, 2016). Moreover, the hiPS-CMs can be formed into a two-dimensional sheet that is electrically coupled and contracts synchronously as a functional cluster, which are properties that allow us to evaluate cardiac contraction and conduction (Izumi-Nakaseko et al, 2017;Pointon et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

Isobe

Honda

Komatsu³

et al. 2018

J. Toxicol. Sci.

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We used motion field imaging to characterize the conduction and contraction of a sheet of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs). A hiPS-CMs sheet of 2.8 mm × 2.8 mm allowed us to simultaneously measure the conduction and the contraction properties in the same cells. Pharmacological responses in the hiPS-CMs of four typical cardiac functional modulators, Na channel blocker (lidocaine), Ca channel blocker (diltiazem), gap-junction inhibitor (carbenoxolone), and β-adrenergic stimulator (isoproterenol), were investigated, and the results were compared to those found using the isolated guinea-pig heart model perfused by the Langendorff method. The conduction speed of excitation waves in hiPS-CMs was decreased by lidocaine, diltiazem, and carbenoxolone, and increased by isoproterenol, and these results were in accordance with the changes in the conduction parameters of electrocardiogram (QRS duration, PR interval, and P duration) in the Langendorff guinea-pig heart model. The maximum speeds for contraction and relaxation, which respectively represent the contraction and relaxation kinetics of hiPS-CMs, were decreased by lidocaine and diltiazem, and increased by isoproterenol. These results also corresponded to alterations in the contractile and relaxation parameters found by measuring left ventricular pressure (LVdP/dt and LVdP/dt) in the Langendorff guinea-pig heart model. From these lines of evidence, it was suggested that hiPS-CMs enable us to evaluate the cardiac toxicities associated with conduction disturbance or contractile dysfunction, and thereby would be useful as an integrated assessment of cardiac function.

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CSAHi study: Detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes

Cited by 38 publications

References 39 publications

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

Electrophysiological characterization of drug response in hSC-derived cardiomyocytes using voltage-sensitive optical platforms

Conduction and contraction properties of human iPS cell-derived cardiomyocytes: analysis by motion field imaging compared with the guinea-pig isolated heart model

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